Neurodon LLC proposes to conduct lead optimization and candidate-seeking activities on a novel series of neuroprotective small molecules that shows efficacy in a transgenic model of Alzheimer?s disease (AD). AD is a leading cause of death in the United States, with some estimates ranking it as high as third behind cardiovascular disease and cancer. Despite the enormity of this national public health burden, the therapeutic options are very limited. The few approved therapies treat only symptoms, and there are no disease-modifying therapies approved. All of the recent clinical trials have failed or are not meeting efficacy endpoints. With this patient population set to almost triple over the next 30 years, there is a dire need for disease-modifying therapies. Neuron loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in patients, and a major cause of brain cell death in AD is endoplasmic reticulum (ER) stress- induced apoptosis caused by intracellular Ca2+ dyshomeostasis. Neurodon?s patented, small molecule positive allosteric modulators (PAMs) of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), rescue brain cells in vitro and in vivo, improve memory and cognition in the APP/PS1 double transgenic mouse model of AD, and reduce ER stress markers in vivo, enabling biomarker-driven drug discovery and an improved probability of clinical success. Our Phase 1 research met the technical milestone of developing molecules with improved in vitro profiles when compared to our previous proof-of-concept compounds. We developed 5 new PAMs with improved efficacy in an in vitro Alzheimer?s model, sub- micromolar potencies in neuroprotection assays, and improved physicochemical properties. In this proposal, we will again partner with the medicinal chemistry expertise and facilities at Northwestern University. We have also added additional experts to the team in Alzheimer?s models, SERCA biology, and behavioral animal models. Our goal of identifying development molecules for Alzheimer?s disease will be accomplished by pursuing the following Aims: 1) Perform lead optimization of SERCA2b PAMs via iterative medicinal chemistry synthesis. 2) Perform in vitro profiling in neuroprotective and synaptoprotective assays to measure potency and efficacy of SERCA2b PAMs. 3) Perform candidate-seeking activities to identify SERCA2b PAMs with drug- like properties. 4) Perform essential in vivo characterization studies on lead SERCA PAMs in the APP/PS1 transgenic mouse model of AD. The results of these Aims will be the identification of candidate molecules to progress into IND-enabling studies at Neurodon.